Antiviral drugs

Different living organisms

Antiviral Drugs Viruses are infectious agents that need host cell in order to survive and multiply. Their structure are simple and designed to protect them from environment and to facilitate their entry into cells. They have Many different shapes

1- Capsid : protein coat surrounding nucleic acid (core) Structure of the virus It consists of : 1- Capsid : protein coat surrounding nucleic acid (core) 2- Core consist of nucleic acid which is either DNA or RNA . The combination of capsid and core is called nucleocapsid 3- Lipid membrane may be present. the complete viral particle is called viron Lipid membrane Capsid

Life cycle of viruses

Replicative cycles of herpes simplex virus, an example of a DNA virus, and the probable sites of action of antiviral agents.

Replicative cycles of influenza, an example of an RNA virus, and the sites for effects of antiviral agents.

DNA viruses RNA viruses Replicate in nucleus Classification of the Viruses DNA viruses RNA viruses DNA Replicate in nucleus Host RNA- dependant DNA polymerase enzyme DNA → m-RNA → protein synthesis RNA Replicate in cytoplasm Using viron Reverse Transcriptase enzyme RNA → ss DNA → ds DNA→ m-RNA → protein synthesis Antiviral Drugs A- Antiviral against DNA virus - change sugar - change base B- Antiviral against RNA virus - Against flu virus - Against HIV virus - Against Hepatitis C virus

1- Antiviral drugs used against DNA viruses Inhibitors of DNA polymerase A) Changes in Sugar Acyclovir zovirax® MOA Acyclovir is phosphorylated by viral thymidine kinase → monophosphate → then by cellular thymidine kinase → triphosphate (active form) The active forms: - Incorporated in viral DNA chain terminate chain elongation (no 3’OH) - competitively inhibits viral DNA polymerase leading to arrest of viral DNA replication Selectivity of acyclovir to viral thymidine kinase is 200 times that of mamalian enzyme therefore in normal uninfected cells it remains as prodrug USES: Herpes Simplex

MOA B) Changes in heterocyclic ring In contrast to Acyclovir these drugs are phosphorylated equally by viral and cellular thymidine kinase → less selective → more toxic side effects First they are activated by phosphorylation with host cell thymidine kinase to the triphosphate active form → 1- inhibit viral DNA polymerase 2- are incorporated in viral DNA → altered DNA , faulty protein synthesis :

Iodoxuridine Ribavarin Virazole® 1)Antimetabolite for thymidine 2) Antimetabolite forguanosine Uses: Topical treatment of herpes acts against DNA and RNA viruses Uses : Broad spectrum : influenza A & B Hepatitis C Iodoxuridine Ribavarin Virazole®

Ribavirin mechanism of action Ribavirin is a guanine analog that is phosphorylated by adenosine kinase to its most active form, ribavirin-triphosphate. This compound inhibits viral RNA-polymerase preferentially at therapeutic doses by competing with adenosine-triphosphate and guanine-triphosphate for binding sites at the polymerase, as well as inhibiting transferases necessary for the addition of guanine.

4) Antimetabolite for Cytosine: 3) Antimetabolite for Adenosine: Fludarabine Fludara® cancer ther. Isolated Streptomyces antibioticus First studied as anticancer drug Interfere with DNA synth Rapid metab. adenosine deaminase 4) Antimetabolite for Cytosine: Cytarabine (ARA-C) Cytarabin®, Cytosar®,

2- Antiviral drugs used against RNA viruses, a) flu viruses Structure of influenza virus 1- Nucleocapsid contains RNA 2- Nucleocapsid is surrounded by envelope formed of 2 glycoproteins: Neuraminidase :degrades mucous layer in host respiratory tract enhancing penetration of virus Haemaglutinin : binds viron to RBCs causing haemaglutination ( acidic condition)

2- Antiviral drugs used against RNA viruses, A) Flu viruses a) Ion channel disruptors Rimantadin Amantadin Adamin® MOA Inhibit penetration of virus to host cell and uncoating of viral nucleic acid A- at low concentration ; it inhibits replication of virus by blocking a viral ion channel protein B- at high concentration it prevents the acidic environment needed for haemaglutinin S.E CNS : nervousness, headache, drowsiness, rimantadine has fewer side Effects due to its extensive biotransformation USES prevention and treatment of influenza A virus especially A2 strain(asian influenza which is fatal) and have no effects on influenza B

Oseltamivir Tamiflu® Inhibits viral neuraminidase enzyme b) Neuraminidase inhibitors Oseltamivir Tamiflu® (“Take my flu”) Zanamivir Relenza® Oseltamivir Tamiflu® MOA Inhibits viral neuraminidase enzyme it may be given as preventive measure either during a community outbreak or following close contact with an infected individual - USES: influenza A ( avian flu) and influenza B

Binding of oseltamivir to NA Hydrophobic pocket Ester moiety is essential For oral activity as it`s A prodrug Basic centre better binding than DANA

2- Antiviral drugs used against RNA viruses, B) HIV viruses a) Nucleoside Reverse transcriptase inhibitors Zidovudine Azidothymidine AZT MOA Antimetabolite for thymidine Phosphorylation of 5’-OH by cellular thymidine kinase → tri-PO4 form → competitive inhibition of reverse transcriptase needed in viral replication The 3’- azido group prevents formation of 5’3’- phosphodiester bond causing DNA chain termination USES AIDS

b) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Binds directly to RT Nevirapin Viramune® Efavirenz / Sustiva Stocrin® FDA 1998 Already resistance J Med Chem 2004, 5923 activity resist strains Wild type RT mutated

c) Protease Inhibitors The HIV-1 protease is an enzyme crucial for the maturation and assembly of infectious viral particles

Saquinavir Fortovase® Ritonavir Norvir® -FDA March 1996, now many resistant strains -Ritonavir inhib. 3A4 isozyme of CypP450 Used in combi. with other protease inhib. to suppress their metab. Indinavir Crixivan® Nelfinavir Viracept®

2- Antiviral drugs used against RNA viruses, C) Hepatitis C viruse a) Viral penetration inhibition Interferon Intron® Are small natural proteins released by infected cells in response to foreign invaders to protect uninfected cells It is an early defense mechanism before antibody formation MOA 1- inhibition of viral penetration 2- inhibition of transcription and translation of virus 3- activate the formation of cellular inhibitory proteins to terminates the production of viral nucleic acid 4- inhibition of viral assembly USES: recombinant DNA methods are used to generate interferon 1-Chronic hepatitis C and B

2- Antiviral drugs used against RNA viruses, C) Hepatitis C viruse b) RNA Polymerase inhibitor Sofosbuvir (brand names Sovaldi,Hepcinat, Resof) is a nucleotide analog used in combination with other drugs for the treatment of hepatitis C virus (HCV) infection. It has been marketed since 2013. Mode of action: It inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA. Use: Sofosbuvir is used for the treatment of chronic hepatitis C, genotypes 1, 2, 3, and 4, in combination with interferon and ribavirin, or with ribavirin alone. Side effects : Fatigue, headache, nausea, rash, and irritability